This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project entails a detailed study of the interaction of the methyltransferases with the substrate DNA. Though the details of catalysis by DNA cytosine-5 methyltransferases are currently known in great detail, the conformational changes that happen before the chemistry takes place have not yet been described. The mechanism by which DNA cytosine-5 methyltransferases target a particular cytosine for extrusion and later methylation is unknown. Hence our goal is to obtain structures of early intermediates of M.HaeIII bound to DNA before the catalysis occurs.